Compositions and methods for producing sedative - tranquilizing activity with malonamidic acid esters



United States Patent Ofiicc CDMPOSITIONS AND METHODS FOR PRODUCINGSEDATIVE -TRANQUHJZING ACTIVITY WITH MALONAMIDIC ACID ESTERS BernardLoev, Broomall, and Edward Macho, Philadelphia, Pa., assignors to SmithKline & French Laboratories, Philadelphia, Pa., a corporation ofPennsylvania No Drawing. Filed Feb. 11, 1966, Ser. No. 526,712

Int. Cl. A611: 27/00; C07c 103/20 U.S. Cl. 424-309 Claims ABSTRACT OFTHE DISCLOSURE Sedative-tranquilizer compositions and methods employingmalonamidic acid esters.

FORMULA I R is hydrogen, chloro, bromo, fluoro, trifluoromethyl, nitro,lower alkyl, lower alkoxy, lower alkoxycarbonyl or the like;

R is lower alkyl and R is lower alkyl having 2-3 carbon atoms.

The malonarnidic acid esters of Formula I may be used as the dl mixtureor as the separated d or 1 optical isomers.

The preferred compositions of this invention contain as the activeingredient a malonamidic acid ester of Formula I in which R is hydrogenand R is ethyl.

A particularly advantageous composition of this invention consists of,in dosage unit, a pharmaceutical carrier and methyla-ethyl-wphenylmalonamidate.

The compositions of this invention contain a malonamidic acid ester ofFormula I in an amount of from about 125 mg. to about 1000 mg,preferably from about mg. to about 500 mg. per dosage unit.

The pharmaceutical carrier may be, for example, either a solid or aliquid. Exemplary of solid carriers are lactose, magnesium stearate,terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin oracacia. Exemplary of liquid carriers are peanut oil, olive oil, sesameoil and water. Similarly, the carrier or diluent may include a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax.

A wide variety of pharmaceutical forms can be em- Patented Aug. 19, 1969ployed. Thus, if a solid carrier is used, the preparation can betableted, placed in a hard gelatin capsule or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 gm. If a liquid carrier is used,the preparation may be in the form of a soft gelatin capsule or a liquidsuspension.

A method in accordance with this invention comprises administeringinternally to an animal organism in an amount sufficient to producesedative-tranquilizing activity a malonamidic acid ester of Formula I.The active ingredient will be administered in a dosage unit form asdescribed above. The route of administration may be orally orparenterally, the oral route being preferred. Advantageously, the activeingredient will be administered in a total daily dosage of from aboutmg. to about 3000 mg, preferably from about 250 mg. to about 1000 mg.When the administration is carried out as described above asedative-tranquilizing activity is produced.

The new methyl a-ethyl-a-phenylmalonamidates which are also objects ofthis invention are represented by the following formula:

FORMULA II in which R is hydrogen, chloro, bromo, fluoro,trifluoromethyl, nitro, lower alkyl, lower alkoxy, lower alkoxycarbonylor the like.

The compound of Formula II in which R is hydrogen is particularlyadvantageous. The activity of this compound in the test in rats foractivity against Metrazol induced convulsions, which is activityindicative of tranquilizers, demonstrates the superior properties of themethyl ester over the next higher alkyl esterf'that is, the ethyl ester.The ED is the dose at which 50% of the animals are protected againstMetrazol induced convulsions.

Metrazol antagonism ED50=24 mgJkg. (complete abolition of Metrazolinduced convulsions at this dose in 50% of the animals tested).

0 0 1] J H OH OC I -CNH2 r CH3 ED5u=52 mgJkg. (only partial protectlonfrom Metrazol induced convulsions at this dose in 50% of theam'malstested). i I u CH3CH;,O-O('3CNHz E CH3 Thus, comparing the ED s methyla-ethyl-a-phenylmalonamidate, which is a new compound, is more thantwice as active in this test as ethyl a-ethyl-u-phenyl malonamidate,which is reported as an intermediate in US. 3,104,201. In addition, themethyl ester is advantageous because at 24 mg./kg. it completelyabolished Metrazol induced convulsions in 50% of the animals testedwhile the ethyl ester at 52 mg./kg. provided only partial protection inof the animals tested.

The malonamidic acid esters are prepared by procedures such as thefollowing:

The terms R R and R are as defined above.

According to procedure I, a a-phenylmalonic acid diester is treated witha base sodium methoxide, sodium hydride, sodium hydroxide or potassiumhydroxide to give the anion which is reacted with R -iodide to give thea-R -ot-phenylmalonic acid diester. The diester is saponified to givethe corresponding malonic acid by treating with aqueous sodiumhydroxide. The u-R -a-phenylmalonic acid is treated with aceticanhydride and sulfuric acid to give the2,2-dimethyl-4,6-dioxo-1,3-dioxane which is treated with a sodium loweralkoxide to give the u-R a-phenylmalonic acid mono-lower alkyl ester.The carboxylic acid group is converted to the carbonyl chloride withthionyl chloride and the carbonyl chloride compound is treated withammonia to give the a-R -a-phenylmalonamidic acid ester.

Alternatively, the 2,2-dimethyl-4,6-dioxo-1,3-dioxane is treated withammonia to give the a-R -m-phenylmalonamidic acid which is esterified togive the a-R -a-pheny1- malonamidic acid ester.

According to procedure II, a phenylacetonitrile is treated with sodiumor potassium hydride, followed by R iodide to give the a-R-phenylacetonitrile. This acetonitrile is treated with sodium orpotassium hydride in a solvent, such as tetrahydrofuran, and then carbondoxide is passed into the mixture to give the a-cyano-a-R phenylaceticacid. The carboxylic acid group is esterified, for example, to give themethyl ester with diazomethane or using methyl iodide and sodiumhydroxide. Treating the a-cyano-a-R -phenylacetic acid ester withsulphuric acid gives the a-R -a-phenylmalonamidic acid ester.

The terms lower alkyl and lower alkoxy where used herein denote groupshaving about 1-4 carbon atoms.

The following examples are not limiting but are illustrative of theinvention.

Example 1 Diethyl a-ethyl-a-phenylmalonate (104 g.) is dissolved in 200ml. of water and ml. of methanol and 120 g. of solid sodium hydroxide isadded. The mixture is heated on a steam bath, with stirring, for 17hours. After one hour a white solid forms. Methanol (40 ml.) is added,the mixture is chilled and filtered. The solid material is washed withmethanol and dissolved in about 100 ml. of water. Concentratedhydrochloric acid is added until a pH of 1 is reached. The precipitateis filtered off and Washed with water to give a-ethyl-a-phenylmalonicacid.

To a suspension of 59.0 g. of a-ethyl-a-phenylmalonic acid in ml. ofacetic anhydride is added 4.3 ml. of concentrated sulfuric acid dropwisewith stirring. The mixture is cooled to 10 C. on an ice-bath and 70 ml.of dry acetone is added at 10-12 C. over a period of 10 minutes. Themixture is stirred at room temperature for 75 minutes. The mixture ischilled and filtered. The solid material obtained is washed with coldwater and recrystallized from acetone-water and dried in a vacuum oven 5at 40 C. to give 5-ethyl-2,2-dimethyl-4,6-dioxo-5-phenyl- 1,3-dioxane.

A solution of 30.0 g. of5-ethyl-2,2-dimethyl4,6-dioxo-5-phenyl-l,3-dioxane in 200 ml. ofabsolute methanol is added to a solution of 6.54 g. sodium methoxide in100 ml. of methanol. The mixture is stirred for 15 minutes at roomtemperature, then concentrated to dryness on a Water bath. Water (200ml.) is added and the mixture is filtered. The filtrate is chilled, madestrongly acidic with concentrated hydrochloric acid and filtered to givethe monomethyl ester of u-ethyl-a-phenylmalonic acid.

To 20.0 g. of the monomethyl ester of a-ethy -aphenylmalonic acid isadded 60 ml. of thionyl chloride. The mixture is refluxed, withstirring, for 1.5 hours. The mixture is concentrated and the residue isdissolved in 150 ml. of dry ether. Anhydrous ammonia is passed throughthe solution with stirring for 30 minutes. The mixture is allowed tostand at room temperature for three hours and filtered. The filtrate isevaporated to dryness. The solid residue is dissolved in hot isopropylether, treated with charcoal, filtered and chilled. The precipitate isfiltered off to give methyl u-ethyl-a-phenylmalonamidate.

Alternatively, a mixture of 5.0 g. of diethyl a-ethyl-uphenylmalonateand 100 ml. of methanolic ammonia is heated on a steam bath for fourdays to give, after concentrating and recrystallizing from isopropylether methyl a-ethyl-a-phenyl-malonamidate.

Example 2 A mixture of 24.8 g. of a-(p-chlorophenyDmalonic acid and 30g. of thionyl chloride is heated at reflux. The excess thionyl chlorideis removed in vacuo. The residu is treated with excess ethanol to give,on distillation, diethyl a-(p-chlorophenyl)malonate.

Ten grams of diethyl a-(p-chlorophenyl)malonate is added to a mixture of1.0 g. of sodium and 35 ml. of ethanol at C. Ethyl iodide (6.0 g.) isadded and the resulting mixture is heated at reflux for five hours, thencooled and poured into water. The mixture is extracted with ether. Theether extracts are concentrated and distilled in vacuo to give diethyla-(p-chlorophenyD-aethylmalonate.

A solution of 16.2 g. of sodium hydroxide in 30 ml. of water is added to157g. of diethyl a-(p-chlorophenyD- a-ethylmalonate. The mixture isheated for two hours, then cooled and acidified. Extracting with ether,removing the ether from the extracts, adding petroleum ether to theresidue and filtering gives a-(p-chlorophenyD-aethylmalonic acid.

A mixture of 8.0 g. of a-(p-chlorophenyl)-a-ethylmalonic acid, 9.9 ml.of acetic anhydride, 0.5 ml. of sulfuric acid and 9.9 ml. of acetone isstirred at room temperature for 1.5 hours, then poured o'nto ice. An oilseparates and crystallizes to give 5-(p-chlorophenyl)-5-ethyl-2,2-dimethyl-4,6-dioxo-1,3-dioxane.

To a solution of 1.2 g. of sodium methoxide in methanol is added 6.1 g.of 5-(p-chlorophenyl)-5-ethyl-2,2-dimethyl-4,6-dioxo-1,3-dioxane in 50ml. of methanol. The resulting mixture is stirred at room temperaturefor minutes to give the monomethyl ester ofa-(p-chlorophenyl)-u-ethylmalonic acid.

A mixture of 4.7 g. of the monomethyl ester of a-(pchlorophenyl)-a-ethylmalonic acid and 25 ml. of thionyl chloride isrefluxed for 1.5 hours, then concentrated and dissolved in dry ether.Anhydrous ammonia is passed through the solution at 5 C. The mixture isfiltered; the filtrate is concentrated and the solid residue isrecrystallized to give methyl or (p chlorophenyl) a ethylmalonamidate.

Example 3 Methyl a-ethyl-a-phenylmalonamidate (9.8 g.), prepared as inExample 1, is added to 52 g. of concentrated sulfuric acid at 70 C. Tothe mixture is added a solution of 2.9 ml. of fuming nitric acid in 13ml. of con centrated sulfuric acid for 30 minutes at 0 C. The mixture isstirred for one hour and poured on ice, then extracted with methylenedichloride and concentrated to give a mixture of oand p-isomers whichare separated, by fractional crystallization from carbon tetrachloride,to give methyl a-ethyl-a-(p-nitrophenyl)malonamidate and methyla-ethyl-a-(o-nitrophenyl)malonamidate.

Example 4 By the procedure of Example 1 using, in place of diethyla-ethyl-a-phenylmalonate, the following:

diethyl a-ethyl-a-(o-methoxyphenyl)malonate diethylu-ethyl-a-(m-methoxyphenyl)malonate diethyl u-ethyl-w(p-tolyl)malonatethe products are, respectively:

methyl a-ethyl-u-(o-methoxyphenyl)malonamidate methyla-ethyl-a-(p-methoxyphenyl)malonamidate methyla-ethyl-a-(p-tolyl)malonamidate.

Example 5 By the procedure of Example 2, using in place ofp-chlorophenylmalonic acid, the following:

o-chlorophenylmalonic acid m-chlorophenylmalonic acido-bromophenylmalonic acid m-bromophenylmalonic acid the products are,respectively:

methyl u-(o-chlorophenyl)-a-ethylmalonamidate methyla-(m-chlorophenyl)-u-ethylmalonamidate methyla-(o-bromophenyl)-a-ethylmalonamidate methyl oz- (m-bromophenyl)-a-ethylmalonamidate.

Example 6 p-Trifluoromethylphenylacetic acid (14 g.) is suspended in 50ml. of thionyl chloride and the mixture is heated at reflux for onehour. Volatile materials are removed in vacuo and the residual acidchloride is slowly added to 50 ml. of liquid ammonia. The excess ammoniais allowed to evaporate and the solid residue is washed with Water togive p-trifluoromethylphenylacetamide.

p-Trifluoromethylphenylacetamide (11 g.) is dissolved in 30 ml. ofthionyl chloride and the resulting solution is refluxed for one hour.Excess thionyl chloride is removed by distillation and the residual oilis distilled t give p-trifiuoromethylphenylacetonitrile.

To a mixture of 1.0 g. of sodium in 35 ml. of ethanol at 0 C. is added6.0 g. of p-trifluoromethylphenylacetonitrile. Ethyl iodide (6.0 g.) isadded and the mixture is heated at reflux for five hours, then cooledand poured into water. Extracting with ether and concentrating anddistilling in vacuo gives a-ethyl-p-trifluoromethylphenylacetonitrile.

A mixture of 3.2 g. of a-ethyl-p-trifluoromethylphenylacetonitrile and10 ml. of tetrahydrofuran is added to a suspension of 1.8 g. of 40%potassium hydride (in oil) in 15 ml. of tetrahydrofuran. Carbon dioxideis passed into the mixture. The solvent is removed in vacuo; the residueis dissolved in water and washed with ether. The aqueous solution isacidified with hydrochloric acid. The organic layer is separated andsolvent distilled off to givea-cyano-a-ethyl-p-trifluoromethylphenylacetic acid.

The above prepared acid is treated with an excess of diazomethane inether. The mixture is stirred at room temperature for 30 minutes, thenconcentrated and distilled to give methylu-cyano-u-ethyl-p-trifluoromethylphenylacetate.

Five grams of the above prepared cyano ester is poured into 50 ml. ofconcentrated sulfuric acid at C. The mixture is heated at 90l00 C. for10 minutes, then is poured onto ice. The precipitate is filtered off andrecrystallized from isopropyl ether to give methyl a-ethy1tx-(p-trifluoromethylphenyl)malonamidate.

7 Example 7 By the procedure of Example 6 using, in place ofp-trifluoromethylphenylacetonitrile, the following:

p-ethylphenylacetonitrile p- (t-butyl phenylacetonitrilepfluorophenylacetonitrile m-ethoxyphenylacetonitrile the products are,respectively:

methyl u-ethyl-a- (p-ethylphenyl malonamidate methyl a-ethyl-a- [p-(t-butyl phenyl] malonamidate methylu-ethyl-a-(p-fluorophenyl)malonamidate methyla-ethyl-u-(rn-ethoxyphenyl)malonamidate.

Example 8 A mixture of g. of methyl a-ethyl-a-(p-nitrophenyl)malonamidate (prepared as in Example 3), 30 ml. of methanol and 1 g. ofpalladium-on-charcoal is hydrogenated for about four hours, thenfiltered, concentrated and distilled to give methyla-ethyl-a-(p-aminophenyl)malonamidate.

The above prepared p-aminophenylmalonamidate is diazotized by dissolvingit in a solution of concentrated hydrochloric acid, water and ice andtreating with sodium nitrite in water at about 0 C. Cuprous cyanide inconcentrated hydrochloric acid and water is added at about 0 C. Themixture is stirred at room temperature for two hours, then heated to 60C. Extracting into ether, then concentrating the ether extracts givesmethyl a-ethyl-u- (p-cyanophenyl) malonamidate.

Three grams of methyl u-ethyl-u-(p-cyanomethyl) malonamidate isdissolved in 100 ml. of methanol. Hy drogen bromide is passed into thesolution for minutes. The mixture is filtered and the filtrate isconcentrated, treated with water and warmed on a steam bath. The organiclayer is distilled to give methyl a-(p-methoxycarbonyl)phenyl-a-ethylmalonamidate.

Example 9 Diethyl a-phenylmalonate (5.0 g.) is added to an aqueousethanol solution containing 1.2 g. of sodium hydroxide. Five grams ofpropyl iodide is added and the resulting mixture is heated at reflux forfive hours. The mixture is cooled, then poured into water and extractedwith ether. Concentrating and distilling the ether extracts givesdiethyl a-phenyl-a-propylmalonate.

By the procedure of Example 2, using the above prepared diethyla-phenyl-a-propylmalonate, the product is methylot-phenyl-a-propylmalonamidate.

Example 10 a-Ethyl-a-phenylacetonitrile (100 g.) in 200 ml. oftetrahydrofuran is added to a suspension of 70 g. of 40% potassiumhydride in 500 ml. of tetrahydrofuran. After the hydrogen evolutionceases, carbon dioxide is bubbled in for minutes. The tetrahydrofuran isevaporated in vacuo. The residue is dissolved in water, extracted withether and the aqueous layer is acidified. The resulting oil isa-cyano-a-ethyl-a-phenylacetic acid.

The above prepared cyanoacetic acid is added to one equivalent ofquinine in methanol. On chilling the salt forms and is filtered ofi andrecrystallized several times from chloroform. The salt is treated withdilute hydrochloric acid and extracted out with ether. Evaporating theether from the extracts gives l-wcyano-a-ethylphenylacetic acid.

The combined filtrates of the above resolution are acidified withhydrochloric acid and filtered to give cruded-u-cyano-a-ethylphenylacetic acid. This is dissolved in ether andl-phenylisopropylarnine is added. The resulting salt is recrystallizedfrom chloroform-ether, dissolved in water, acidified with hydrochloricacid and extracted with ether to give the d-a-cyano-u-ethylphenylaceticacid.

The resolved acids are each treated with diazomethane in ether. Afterconcentrating, the methyl ester is isolated as an oil.

Each of the above prepared methyl esters is treated as follows: 5.0 g.is added to 50 ml. of concentrated sulfuric acid at C. The mixture iskept at 90100 C. for ten minutes then poured onto ice. The solid isrecrystallized from isopropyl ether to givel-methyl-u-ethyl-a-phenylmalonamidate and d-methyl-a-phenylmalonamidate.

Example 11 Ingredients: Amounts (mg) Methyl-a-ethyl-a-phenylmalonamidate125 Sucrose Starch 25 Talc 5 Stearic acid 2 The active ingredient andthe sucrose are mixed and granulated with 10% gelatin solution. Thewetted mass is screened and dried. The granules are mixed with thestarch, talc and stearic acid, screened and then compressed into atablet.

One tablet is administered three times a day.

Example 12 A tablet is made as described in Example 11 using as theactive ingredient ethyl a-ethyl-a-phenylmalonamidate (250 mg.).

Example 13 Ingredients: Amounts (mg) Methyl a-ethyl a (pnitrophenyl)malonamidate 300 Lactose 75 The ingredient are screened,mixed and filled into a hard gelatin capsule.

Example 14 Ingredients: Amounts (mg) Methyl a(p-chlorophenyl)-a-ethylmalonamidate 400 Peanut oil 100 The ingredientsare mixed into a slurry and filled into a soft gelatin capsule.

Example 15 Ingredients: Amounts (mg.) Methylu-ethyl-a-phenylmalonamidate 250 Lactose 75 Magnesium stearate 5 Theingredients are mixed and filled into a hard gelatin capsule.

What is claimed is:

1. A dosage unit in the form of a tablet, capsule, troche, lozenge orparenteral solution for administration to pro ducesedative-tranquilizing activity comprising a pharmaceutical carrier andfrom about mg. to about 1000 mg. of a malonamidic acid ester of theformula:

4. A dosage unit according to claim 1 in which said dosage unit is acapsule.

5. A dosage unit according to claim 2 in which said dosage unit is atablet.

6. A dosage unit according to claim 2 in which said dosage unit is acapsule.

7. The method of producing sedative-tranquilizing activity whichcomprises administering internally to an animal organism in an amountsufiicient to produce said activity a malonamidic acid ester of theformula:

nitro, lower alkyl, or lower alkoxy; R is lower alkyl and R is loweralkyl having 2-3 carbon atoms.

8. The method according to claim 7 in which R is hydrogen, R is methyland R is ethyl.

9. The method according to claim 7 in which said malonamidic acid esteris administered orally in a daily dosage regimen of from about mg. toabout 300(lrmg.

10. The method according to claim 8 in which said malonamidic acid esteris administered orally in a. daily dosage regimen of from about 125 mg.to about 3000mg.

OTHER REFERENCES Chem. Abstracts, 59, p. 38200 (1963).

ALBERT T. MEYERS, Primary Examiner S. I. FRIEDMAN, Assistant ExaminerU.S. Cl. X.R.

